Pathophysiology of unilateral pulmonary aspergillosis in an experimental rat model

Becker, Martin; Marie, S. de; Fens, Marcel H.A.M.; Haitsma, Jack J.; Verbrugh, Henri A.; Lachmann, Burkhard; Bakker-Woudenberg, Irma A. J. M.

doi:10.1080/13693780500271749

Cited by 11 publications

(15 citation statements)

References 25 publications

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“…In our laboratory, we developed a model of unilateral IPA in rats that closely mimics the human disease in patients with transient neutropenia (8,9,41). This model is characterized by a transiently neutropenic state, fungal inoculation through the respiratory route, fungal broncho-and angioinvasion, and extrapulmonary dissemination.…”

Section: At Present Voriconazole (Vor) Is the Drug Of First Choice Fmentioning

confidence: 99%

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Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Sande

Mathôt

Kate

et al. 2009

Antimicrob Agents Chemother

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At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA).However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentrationtime curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.Invasive pulmonary aspergillosis (IPA) continues to be a major problem in immunocompromised patients (18). Since voriconazole (VOR) was shown to be superior to amphotericin B (AMB) in a large randomized trial, it became the drug of choice for the treatment of IPA (22, 44). More recently, another class of antifungal agents, the echinocandins, has been used to salvage patients with refractory IPA (44). Echinocandins target 1,3-␤-D-glucan synthesis of most pathogenic fungi. Caspofungin (CAS) was the first drug of this class, and more recently anidulafungin (ANI) has become available. However, despite these new treatment options for IPA, the mortality remains substantial, with mortality rates of 25 to 35% 12 weeks after diagnosis (21, 22). Combination therapy might reduce mortality rates further. From clinical observational studies, it appeared that in 57 to 68% of the favorable results were obtained in patients when combination therapy with VOR and CAS was applied (27,37). In neither of these studies, however, was the combination therapy compared to VOR monotherapy in a randomized fashion.In this respect, preclinical research in animal models of IPA is important for investigating the potency of antifungal agents in combination. In our laboratory, we developed a model of uni...

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Section: At Present Voriconazole (Vor) Is the Drug Of First Choice Fmentioning

confidence: 99%

“…The rat model of aerogenic IPA in transiently neutropenic rats was used, as described previously (8,9,41,42). In short, in neutropenic female RP strain albino rats left-sided invasive IPA was induced by instillation of an A. fumigatus conidial suspension, followed by inhalation.…”

Section: Aspergillus Fumigatus Strainmentioning

confidence: 99%

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Sande

Mathôt

Kate

et al. 2009

Antimicrob Agents Chemother

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“…Injectable glycopeptides and carbapenems were sporadically used to prevent infections due to multi-resistant staphylococci and enterobacteriae (Melchers et al, 1994; Hashimoto et al, 1998; Yonezawa et al, 2000; Benjamim et al, 2005; Steinbach et al, 2006; Tansho et al, 2006; van Vianen et al, 2006; Cramer et al, 2008; Pinchai et al, 2009; Rivera et al, 2009; Petrik et al, 2010, 2012, 2014; Grahl et al, 2011; Martinez et al, 2013; Verwer et al, 2013). Likewise, multi-antibiotic associations were sometimes reported, like the following scheme: ciprofloxacin (660 mg/L) and polymyxin B (100 mg/L) in water, plus IM amoxicillin (40 mg/kg/day) and a single shot of IM gentamicin (6 mg/kg) at time of experimental infection (Leenders et al, 1996; Dams et al, 1999; Becker et al, 2000, 2002a,b, 2003, 2006; Van Etten et al, 2000; Ruijgrok et al, 2001, 2005, 2006). Interestingly, a few authors preconized to dilute halogenated derivatives, like chlorine or iodine, as disinfectants in drinking water (Corbel and Eades, 1977; Xu et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…In spite of recent major advances (Sable et al, 2008; Brown, 2011; Steele and Wormley, 2012; Wüthrich et al, 2012; Drew et al, 2013; Lanternier et al, 2013), there are still many concerns to be addressed: for example, why a particular strain is more virulent than another (Becker et al, 2006)? How to prevent a contamination?…”

Section: Introductionmentioning

confidence: 99%

Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization

Désoubeaux

Cray

2017

Front. Microbiol.

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Invasive aspergillosis has been studied in laboratory by the means of plethora of distinct animal models. They were developed to address pathophysiology, therapy, diagnosis, or miscellaneous other concerns associated. However, there are great discrepancies regarding all the experimental variables of animal models, and a thorough focus on them is needed. This systematic review completed a comprehensive bibliographic analysis specifically-based on the technical features of rodent models infected with Aspergillus fumigatus. Out the 800 articles reviewed, it was shown that mice remained the preferred model (85.8% of the referenced reports), above rats (10.8%), and guinea pigs (3.8%). Three quarters of the models involved immunocompromised status, mainly by steroids (44.4%) and/or alkylating drugs (42.9%), but only 27.7% were reported to receive antibiotic prophylaxis to prevent from bacterial infection. Injection of spores (30.0%) and inhalation/deposition into respiratory airways (66.9%) were the most used routes for experimental inoculation. Overall, more than 230 distinct A. fumigatus strains were used in models. Of all the published studies, 18.4% did not mention usage of any diagnostic tool, like histopathology or mycological culture, to control correct implementation of the disease and to measure outcome. In light of these findings, a consensus discussion should be engaged to establish a minimum standardization, although this may not be consistently suitable for addressing all the specific aspects of invasive aspergillosis.

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“…sojae , A. tamarii and A. nomius [18,19]. Sequence-based approaches include analysis of rDNA ITS and 28S rRNA variable regions [20,21], together with calmodulin and β-tubulin gene regions [7,22,23]. Variability in the latter two genes can be appropriate for resolving closely related Aspergillus species [24].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Aspergillus species on Brazil nut from the Brazilian Amazonian region and development of a PCR assay for identification at the genus level

et al. 2014

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BackgroundBrazil nut is a protein-rich extractivist tree crop in the Amazon region. Fungal contamination of shells and kernel material frequently includes the presence of aflatoxigenic Aspergillus species from the section Flavi. Aflatoxins are polyketide secondary metabolites, which are hepatotoxic carcinogens in mammals. The objectives of this study were to identify Aspergillus species occurring on Brazil nut grown in different states in the Brazilian Amazon region and develop a specific PCR method for collective identification of member species of the genus Aspergillus.ResultsPolyphasic identification of 137 Aspergillus strains isolated from Brazil nut shell material from cooperatives across the Brazilian Amazon states of Acre, Amapá and Amazonas revealed five species, with Aspergillus section Flavi species A. nomius and A. flavus the most abundant. PCR primers ASP_GEN_MTSSU_F1 and ASP_GEN_MTSSU_R1 were designed for the genus Aspergillus, targeting a portion of the mitochondrial small subunit ribosomal RNA gene. Primer specificity was validated through both electronic PCR against target gene sequences at Genbank and in PCR reactions against DNA from Aspergillus species and other fungal genera common on Brazil nut. Collective differentiation of the observed section Flavi species A. flavus, A. nomius and A. tamarii from other Aspergillus species was possible on the basis of RFLP polymorphism.ConclusionsGiven the abundance of Aspergillus section Flavi species A. nomius and A. flavus observed on Brazil nut, and associated risk of mycotoxin accumulation, simple identification methods for such mycotoxigenic species are of importance for Hazard Analysis Critical Control Point system implementation. The assay for the genus Aspergillus represents progress towards specific PCR identification and detection of mycotoxigenic species.

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Pathophysiology of unilateral pulmonary aspergillosis in an experimental rat model

Cited by 11 publications

References 25 publications

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization

Characterization of Aspergillus species on Brazil nut from the Brazilian Amazonian region and development of a PCR assay for identification at the genus level

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